Deciphering the function of naturally occurring peptides in human milk

描述（由申请人提供）：肽形成人体中的大多数信号系统。这些在肠道、大脑、胰腺、皮肤和其他器官中产生的肽具有深远的影响，例如控制食物摄入、新陈代谢、血压、行为、排卵和昼夜节律。在许多情况下，这些信号肽具有可追溯到数亿年进化的共同模式。然而，肽作为治疗性信号传导剂的应用尚未得到充分探索。我们已经表明，通过新的质谱为基础的肽组学方法，超过500肽在乳腺本身的母乳中产生。这些天然存在的肽代表了一类新的食物分子，它们在母亲和婴儿体内具有尚未表征的信号传导功能。我们已经表明，超过10%是同源的已知肽的抗菌和免疫调节功能。其余的功能还有待发现。第一代检测已经发现所鉴定的肽具有抗微生物作用作为一个整体，这些肽抑制了几种致病菌的生长。拟议的研究计划将定义天然存在的牛奶肽的整个范围，它们的不同功能以及哪些特定序列负责。将检查肽的特定生物背景相关作用，包括抗微生物、抗真菌、益生元、抗寄生虫和抗炎作用。研究牛奶中的肽将解开动态和复杂的大分子系统，可应用于婴儿和成人的健康。 我的长期目标是利用营养或食品科学终身教职在一级研究型大学的位置，建立一个高影响力的研究计划，在人类健康。我相信，这项研究计划的核心将旨在了解母乳对婴儿健康的影响，特别是从消化的角度，并利用这种理解来指导所有年龄段的营养和健康。 加州大学戴维斯分校是在该奖项的K99阶段实现本提案目标的首要场所。我在博士期间召集的合作者们。和第一年的博士后工作使这个项目成为可能。加州大学戴维斯分校不仅在Lebrilla博士和Barile博士的实验室提供最先进的分析质谱，而且还能够通过与加州大学戴维斯分校医学院新生儿重症监护室负责人Mark安德伍德博士的合作从婴儿的胃中获取样本。此外，我还与大量合作者建立了网络，以测试牛奶肽在测定中的各种功能。

DESCRIPTION (provided by applicant): Peptides form the majority of signaling systems in humans. These peptides, produced in the gut, brain, pancreas, skin and other organs have far-reaching effects-controlling food intake, metabolism, blood pressure, behavior, ovulation, and circadian rhythms as examples. These signaling peptides have, in many cases, common modalities traceable back hundreds of millions of years in evolution. However, the application of peptides as therapeutic signaling agents has not been fully explored. We have shown, through novel mass spectrometry-based peptidomics methodology, that over 500 peptides are produced in human milk within the mammary gland itself. These naturally occurring peptides represent a new class of food molecules that have as yet uncharacterized signaling functions within the mother and the infant. We have shown that over 10% are homologous to known peptides with antimicrobial and immunomodulatory functions. The rest have yet to be discovered functions. First generation assays have discovered that the peptides identified have antimicrobial actions-as an ensemble, these peptides inhibited the growth of several strains of pathogenic bacteria. The proposed research program will define the entire range of naturally occurring milk peptides, their diverse functions and also which specific sequences are responsible. Peptides will be examined for specific biological- context-relevant actions, including antimicrobial, antifungal, prebiotic, anti-parasitic and anti-inflammatory actions. Investigating milk's peptides will unlock dynamic and complex system of macromolecules that can be applied to infant and adult health. My long-term goal is to leverage a Nutrition or Food Science tenure-track faculty position at a tier-one research university to establish a high-impact research program in human health. I am convinced that the core of this research program will be designed to understand the effects of human milk on infant health, particularly from the perspective of digestion, and use this understanding to guide the nourishment and health of all ages. University of California, Davis, is the premier place to accomplish the aims of this proposal during the K99 phase of the award. The collaborators I have brought together during my Ph.D. and first year of post- doctoral work have made this project possible. UC Davis provides not only state-of-the-art analytical mass spectrometry in Dr. Lebrilla's and Dr. Barile's labs, but also the ability to obtain samples from te stomachs of infants through a collaboration with Dr. Mark Underwood, the head of the neonatal intensive care unit at the UC Davis Medical School. In addition, I have networked with a large number of collaborators to test the milk peptides for a variety of functions in assays.